Biography

Dr. Hsing received an M.P.H. in biostatistics from the University of California at Los Angeles in 1981, and a Ph.D. in epidemiology from The Johns Hopkins School of Hygiene and Public Health in 1988. She conducted postdoctoral research at the School of Hygiene and Public Health before joining the NCI in 1989. Dr. Hsing is a member of the Hormonal and Reproductive Epidemiology Branch, and an adjunct professor of Department of Epidemiology and Department of Urolgoy at George Washington University. She is a member of the epidemiology committee of the International Consortium for Urologic Diseases, a member of the Biological Specimen Advisory Committee of the American Cancer Society, a member at the American Epidemiological Society, a member of the Editorial Board of Cancer Epidemiology Biomarkers and Prevention, and a Fellow of the American College of Epidemiology. Dr. Hsing received an Intramural Research Award for innovative research in prostate cancer and an award for promoting research quality as the Chair of the DCEG Committee for Technical Evaluation of Protocols, and the NIH Merit Award for her contribution to etiologic research on prostate cancer, and a DCEG Outstanding Mentoring Award.

Research Interests

We are carrying out population-based, interdisciplinary studies to investigate the determinants of hormone-related cancers, particularly of the prostate and biliary tract. Risk of these cancers is being evaluated in relation to endogenous and exogenous hormones, lifestyle factors, and genetic susceptibility and their interactive effects. Methodologic studies are examining hormone levels in serum and tissues, polymorphisms in targeted genes and cellular proliferation, and lifestyle factors in an effort to increase our understanding of hormonal carcinogenesis. We are also assessing these variables in relation to differences in cancer rates among racial groups.

Prostate Cancer

Little is known about the etiology of prostate cancer, although it is the most commonly diagnosed cancer among men in the United States. Despite a similar prevalence of latent prostate tumors around the world, incidence rates for clinical prostate cancer in western men are 30 to 50 times higher than those for Asian men. This finding and data from migrant studies suggest a role for environmental factors in promoting late-stage disease. To improve our understanding of prostate cancer etiology and to identify preventive measures, we conducted a population-based case-control study of prostate cancer in Shanghai, China, where the reported incidence for clinical prostate cancer is the lowest in the world, but is rising rapidly.

Results thus far have provided important etiologic leads concerning the substantial racial differences in prostate cancer risk. Analyses of the interview data suggest that increased risk is associated with higher levels of education, a larger waist or smaller hips, a higher waist-to-hip ratio, and a higher intake of total calories, red meat, and animal fat and protein, while a reduced risk is associated with higher consumption of allium vegetables, peppers, and mushrooms. Risk was not associated with smoking, alcohol use, tea drinking, family history of prostate cancer, sexual behavior, physical activity, body mass index, weight history, or obesity in adolescence. Among the factors examined, a high waist-to-hip ratio (an indicator of central obesity) is associated with the strongest risk. Assuming that central obesity is a causal factor, a waist-to-hip ratio higher than the first quartile (>0.87) can explain 43% (95% CI 22% to 64%) of the cases in Shanghai, and 23% of the 50 to 60-fold difference in incidence rates between the United States and China. Special efforts are being made to evaluate further the roles of energy, fat type, and individual fatty acids. In addition, we are assessing the potential protective effect of tea polyphenols and isoflavones, chemicals with weak anti-estrogenic activity found in soy foods.

Most of the risk factors for prostate cancer, such as central obesity, a western diet, and physical activity, may have a hormonal basis. We are investigating this hypothesis in biochemical and molecular studies that may define more clearly relevant exposures and biologic mechanisms. Results thus far show that higher serum levels of insulin and insulin-like growth factor I (IGF-1) and lower serum levels of IGF binding proteins (IGFBP-1 and IGFBP-3) are associated with a significantly increased risk. Analyses are correlating serum levels of hormones, IGFs, insulin, and leptin with anthropometric factors and physical activity, which may shed light on hormonal and other mechanisms of prostate carcinogenesis.

Environmental factors alone are unlikely to explain all of the racial difference in prostate cancer risk. We are therefore assessing the role of several genetic markers involved in the regulation of androgens, including the androgen receptor (AR) and the steroid 5 alpha-reductase type II (SRD5A2) genes. An increased risk was associated with a shorter CAG repeat length in the AR gene, while no association was found with polymorphic markers in the SRD5A2 gene, including A49T, V89L, R227Q, and TA repeats. We are planning to evaluate other genes involved in the androgen metabolic pathways, including CYP17, CYP19, CYP3A4, HSD3", HSD3$, and HSD17$. We are also investigating whether somatic mutations of the SRD5A2 gene are associated with tumor aggressiveness and prostate cancer prognosis.

Analyses will be initiated to evaluate whether 5 alpha-reductase activity, as measured indirectly by serum levels of androstenediol glucuronide and polymorphisms of the SRD5A2 gene, is determined largely by genetics or modulated through lifestyle factors. In addition, circulating hormone levels will be correlated with genetic polymorphisms and lifestyle factors to evaluate how phenotypic and genotypic factors interact to modulate risk.

It is unclear whether serum levels of hormones reflect intraprostatic androgenicity. To address this issue, we are carrying out a methodologic study to assess the correlation among hormones measured directly in the prostate, serum hormone levels, and polymorphisms of hormone-related genes. The study is taking into account factors, such as age, smoking, and body size, that might alter serum-tissue correlations. To better estimate total intraprostatic androgenicity, prostate tissue will be measured directly for levels of androgen receptor and its associated protein, such as ARA 75 and 55. Because this study is investigating androgenicity in prostate tissue directly, it will help guide future epidemiologic studies of prostate cancer.

We are also conducting a prostate cancer survey in Accra, Ghana to assess the burden of prostate cancer among West African men, who share genetic ancestry but have vastly different lifestyle factors compared to African Americans, a group which has one of the highest prostate cancer risks in the world. Through medical records review, one study component aims to enumerate and characterize clinical prostate cancer cases to estimate clinical prostate cancer incidence in Accra. In the second component of the study, 1,000 healthy men aged 50-74 years randomly selected from the population will undergo interview, blood collection, and prostate cancer screening with digital rectal examination and prostatic specific antigen blood test in order to estimate the extent of prostate cancer burden in this unscreened population.

Biliary Tract Cancers

Cancers of the biliary tract include tumors arising from the gallbladder, extrahepatic bile duct, and ampulla of Vater. These malignancies are relatively uncommon and little is known about their etiology. Previous analytic studies have been limited by small numbers, proxy interviews, and inability to evaluate risk separately by anatomic subsite.

During the last 25 years, biliary tract cancer incidence has increased more rapidly than any other malignancy in Shanghai, suggesting a change in prevalence of risk factors. To identify these factors, we are conducting a large-scale, population-based case-control study to evaluate risks associated with gallstones, bacterial infections of the biliary tract, dietary factors, obesity, use of tobacco and alcohol, reproductive factors, and exogenous hormones. With 900 cancer cases and 1,000 population controls, the study should provide sufficient statistical power to investigate separately the etiology of each subsite.

Since gallstone disease tends to cluster in families, we will attempt to evaluate whether genetic predisposition plays a role in biliary tract cancer. Analyses will examine family history, polymorphisms of susceptibility genes, and genetic interactions with lifestyle factors.

Keywords

prostate cancer, biliary tract cancers, hormones, androgens, androgen receptor, 5-alpha reductase, obesity, insulin, insulin-like growth factors, diet, genetic polymorphism, methodologic studies, racial/ethnic variation

Selected Publications

• Hsing AW, et al. "Serum levels of insulin and leptin in relation to prostate cancer risk." J Natl Cancer Inst 2001; 93:783-789.
• Hsing AW. "Hormones and prostate cancer: what's next?" Epidemiol Rev 2001; 23:42-58.
• Hsing AW, et al. "Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China." Cancer Res 2000; 60:5111-5116.
• Hsing AW, et al. "Body size and prostate cancer: a population-based case-control study in Shanghai, China." Cancer Epidemiol Prev Biomarkers 2000; 9:1435-1441.

Collaborators

DCEG Collaborators

• Linfang Hou, M.D., Ph.D.; Lori Sakoda, MPH; Shih-Chen Chang, Ph.D.; Phil Rosenberg, Ph.D.; Jinbo Chen, Ph.D.; Wen-Yi Huang, Ph.D.; Richard Hayes, Ph.D.; Susan Devesa, Ph.D.; Joseph Fraumeni, Jr., M.D.; Thomas Fears, Ph.D.; James Goedert, M.D.; Gloria Gridley, M.S.; James Lacey Jr., Ph.D.; Martha Linet, M.D.; Katherine McGlynn, Ph.D.; Charles S. Rabkin, M.D.

Other NCI Collaborators

• Kenneth Buetow, Ph.D.; Ya-Yu Tsai, Ph.D.; Tzu-Ling Tseng, Ph.D.

Other Scientific Collaborators

• Hans-Olov Adami, M.D.; Anders Ekbom, M.D.; Olof Nyren, M.D., Karolinska Institute, Stockholm, Sweden
• Stephen Barnes, Ph.D., University of Alabama, Birmingham, AL
• William Blot, Ph.D.; Joseph McLaughlin, Ph.D., International Epidemiology Institute, Rockville, MD
• Zoran Culig, M.D., Ph.D., University of Innsbruck, Innsbruck, Austria
• Angelo DeMarzo, M.D., Ph.D.; William Isaacs, Ph.D., Johns Hopkins Hospital, Baltimore, MD
• Capri-Mara Fillmore, M.D., Medical College of Wisconsin, Milwaukee, WI
• Peter Carroll, M.D.; Marion Lee, Ph.D., University of California at San Francisco, San Francisco, CA
• Chawnshang Chang, Ph.D., University of Rochester, Rochester, NY
• Chien-Jen Chen, Ph.D., National Taiwan University, Taipei, Taiwan
• Chu Chen, Ph.D., University of Washington, Seattle, WA
• Streamson Chua, M.D., Ph.D., Columbia University, New York, NY
• Pierluigi Cocco, M.D., University of Cagliari, Italy
• Jei Deng, M.D.; Jin Fan, M.D.; Yu-Tang Gao, M.D., Shanghai Cancer Institute, Shanghai, China
• James Dick, M.D., The Johns Hopkins University, Baltimore, MD
• James Fox, M.D., Massachusetts Institute of Technology, Cambridge, MA
• Tianquan Han, M.D., Ph.D., Raijin Hospital, Shanghai, China
• George Hemstreet, M.D., University of Oklahoma, Oklahoma City, OK
• Kai-Li Liaw, Ph.D., University of Pittsburgh, Pittsburgh, PA
• Paul Levine, M.D., George Washington University, Washington, D.C.
• Lee-Jane Lu, Ph.D., University of Texas, Galveston, TX
• Lene Mellemkjaer, Ph.D., Danish Cancer Registry, Copenhagen, Denmark
• K. F. Mostofi, M.D.; Isabell Sesterhenn, M.D., Armed Forces Institute of Pathology, Washington, D.C.
• Asif Rashid, M.D., Ph.D., M.D. Anderson Cancer Center, Houston, TX
• Juergen Reichardt, Ph.D.; Frank Stanczyk, Ph.D., University of Southern California, Los Angeles, CA
• Howard Strickler, M.D., Albert Einstein College of Medicine, Bronx, NY
• Run-Tian Wang, M.D., Beijing Medical University, Beijing, China
• Jianfeng Xu, M.D., Dr.PH., Center for Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
• Ling Xu, M.D., Peking Union Memorial Hospital, Beijing, China
• C. S. Yang, Ph.D., Rutgers University, Piscataway, NJ
• Edward Yeboah, M.D., Korle-Bu Hospital,Ghana